Project Summary Sepsis is a life threatening illness characterized by an overwhelming inflammatory response to infection, and the development of hyperglycemia during sepsis is associated with increased organ dysfunction and mortality. The factors contributing to the development of hyperglycemia are not completely understood but recently our laboratory demonstrated that nutritional support, in the form of parenteral infusions of dextrose, can have important effects on metabolic outcomes in sepsis. We found that both septic insult and dextrose infusions were necessary for the development of metabolic dysfunction and hyperglycemia in mouse models of sepsis and that development of hyperglycemia was associated with increased inflammation and increased mortality. Our objective for this proposal is to understand how the route of delivery of nutritional support (enteral or parenteral) influences the development of metabolic dysfunction in sepsis. Critically ill patients receive enteral nutrition in the form of tube feeds, and although the use of total parenteral nutrition has declined, parenteral dextrose infusions remain common in maintenance fluids and as medication carriers. We hypothesize that enteral administration of dextrose during sepsis will be associated with improved metabolic and inflammatory outcomes compared to parenteral infusion. We will test this hypothesis with the following aims: (1) We will determine the effect of route of nutritional support on development of metabolic dysfunction and inflammation in murine endotoxemia with the use of the frequently sampled intravenous glucose tolerance test, and (2) We will determine the roles of the incretin hormones gastric inhibitory peptide and glucagon like peptide 1 in improving glycemic control during sepsis and how they differ based on route of nutritional support. Together these studies will provide the platform for future development of translational investigations targeting improvement in outcomes of critically ill patients. This proposal will allow the candidate, a physician scientist in-training, the opportunity to develop further as a translational scientist and bridge between animal models and human studies. The candidate has a recent background in clinical research and through lab experience and meetings with his mentors will be gaining experience in developing animal models to answer questions that are otherwise difficult to answer solely in human studies. Additionally, he will undertake Master's degree training in Clinical Research with a focus in Translational Science which will strengthen his background in both basic science and clinical research. His mentors, Drs. O'Donnell and McVerry have extensive resources and knowledge to allow him to develop as a translational scientist and he will be well-supported by the Division of Pulmonary, Allergy, and Critical Care Medicine, which has demonstrated strong commitment to his development as an independent clinician investigator.